Myelodysplastic Syndromes“What is on the horizon?”

Rami Komrokji, MDSenior Member & Professor of Oncologic Sciences

Section Head – Leukemia & MDSVice Chair - Malignant Hematology Department

H Lee Moffitt Cancer Center & Research InstituteTampa, Florida

Myelodysplastic Syndromes (MDS)

• A group of malignant hematopoietic neoplasms characterized by1

– Bone marrow failure with resultant cytopenia and related complications

– Evidence of clonality by cytogenetic abnormalities or somatic gene mutations.

– Dysplastic cytologic morphology is the hallmark of the disease

– Tendency to progress to AML

• Overall incidence 3.7-4.8/100,0002

– In US (true estimates ≈37,000-48,000)

• Median age: 70 yrs; incidence: 34-47/100,000 >75 yrs3

AML = acute myeloid leukemia.1. Bennett J, et al. The myelodysplastic syndromes. In: Abeloff MD, et al, eds. Clinical Oncology. New York, NY: Churchill Livingstone; 2004:2849-2881. 2. SEER data. 2000-2009. 3. SEER 18 data. 2000-2009.

Non-clonal ICUS

CHIP CCUS LR-MDS HR-MDS

Traditional ICUS MDS by WHO 2016

Clonality

Dysplasia

Cytopenias

Overall Risk

+ – ++ ++ ++

–/+ – – + ++

– + + + ++

Very Low Very Low Low (?) Low High

BM Blast %< 5% < 5% < 5% < 5% 5-19%

Are these two the same?Does morphologic dysplasia matter?

CCUS = clonal cytopenias of undetermined significance; ICUS = idiopathic cytopenias of undetermined significance; CHIP = clonal hematopoiesis of indeterminate potential; LR = lower risk, HR = higher risk

MDS the spectrum?

Risk Groups for the IPSS-RRisk group Points % of Patients Median survival, years

Time until 25% of patients develop AML,

years

Very low ≤ 1.5 19 % 8.8 Not reached

Low > 1.5 – 3 38 % 5.3 10.8

Intermediate > 3 – 4.5 20 % 3.0 3.2

High > 4.5 – 6 13 % 1.6 1.4

Very High > 6 10 % 0.8 0.73

100

Overall Survival, years

Pa

tie

nts

, %

00 2 4 6 8 10 12

20

40

60

80

Pa

tie

nts

, %

Time to AML Evolution, years

0 2 4 6 8 10 12

100

0

20

40

60

80

Very low Low Int High Very high

Adapted from Greenberg PL, et al. Blood. 1997;89:2079-2088.

Somatic Gene Mutations Improve Precisionof the IPSS-R

Bejar R. Haematologica 2014; 99: 956.

Summary of Risk Stratification

• very low risk R-IPSS +/- 1 HR somatic mutation (SM).

• Low risk R-IPSS no HR SM• Very low/low/intermediate R-IPSS with SF3B1 SM.

• Low risk R-IPSS + 1 HR SM.• Intermediate risk R-IPSS no HR SM.

• Intermediate risk R-IPSS + HR SM• Very high and high risk R-IPSS.• Complex monosomy karyotype.• > 3 HR SM.• P53 mutation.

Anemia Management Algorithm in LR-MDS 2019

Fenaux P, et al. Lancet Oncol. 2009;10:223-232..

Epo<200mU/mL

<2U RBC/mo

ESA

Non-del5q

AZA 5 dayLEN+/- Epo

Del (5q)

Iso- or +1

LenalidomideDel5q

Epo>200mU/mL

>2U RBC/mo

Age

>60 <60

SF3B1 Mu+ No SGM or SF3B1 Mu-

MDS > 24 mos HLA-DR15+,+8

ISTNon-del5qpathway

*SGM, somatic gene mutation.

Excess Smad2/3 Signaling Suppresses Late-Stage RBC Maturation in MDS

TGF-β ligands (e.g. GDF15,

GDF11, BMP6, activin A)

negatively regulate late

erythropoiesis

Bone marrow microenvironment

Luspatercept releases maturation block

Baso E Poly E Ortho E Reticulocyte RBC

SCFIL-3EPO

BFU-E CFU-E Pro-E

EPO-responsive

EPO-dependent

EPO

8–64 cells500 cells

Sustained Hb increase Rapid Hb increase

• Mobilizes cells from precursor pools into blood• Effect relies on continuous formation of

late-stage precursors from earlier progenitors

Zhou L, et al. Blood. 2008;112:3434-3443.

The MEDALIST Trial: Results of a Phase 3, Randomized, Double-Blind,

Placebo-Controlled Study of Luspatercept to Treat Patients With Very Low-,

Low-, or Intermediate-Risk Myelodysplastic Syndromes (MDS) Associated

Anemia With Ring Sideroblasts (RS) Who Require Red Blood Cell (RBC)

Transfusions

Pierre Fenaux, Uwe Platzbecker, Ghulam J. Mufti, Guillermo Garcia-Manero, Rena Buckstein, Valeria Santini, María Díez-Campelo, Carlo Finelli, Mario Cazzola, Osman Ilhan, Mikkael A. Sekeres, José F. Falantes, Beatriz Arrizabalaga, Flavia Salvi, Valentina Giai, Paresh Vyas, David Bowen, Dominik Selleslag, Amy E. DeZern, Joseph G. Jurcic, Ulrich Germing, Katharina S. Götze, Bruno Quesnel, Odile Beyne-Rauzy, Thomas Cluzeau, Maria Teresa Voso, Dominiek Mazure, Edo Vellenga, Peter L. Greenberg, Eva Hellström-Lindberg, Amer M. Zeidan, Abderrahmane Laadem,

Aziz Benzohra, Jennie Zhang, Anita Rampersad, Peter G. Linde, Matthew L. Sherman, Rami S. Komrokji, Alan F. List

MEDALIST Trial

Luspatercept

• Luspatercept is an investigational first-in-class erythroid maturation agent that neutralizes select TGF-β superfamily ligands to inhibit aberrant Smad2/3 signaling and enhance late-stage erythropoiesis in MDS models1

• In a phase 2 study in LR, non-del(5q) MDS, luspatercept yielded a high frequency of transfusion reduction or RBC-TI in patients with MDS-RS vs other subtypes2

ActRIIB, human activin receptor type IIB; IgG1 Fc, immunoglobulin G1 fragment crystallizable; RBC-TI, red blood cell transfusion independence; RS, ring sideroblasts; TGF-β, transforming growth factor beta.

1. Suragani RN, et al. Nat Med. 2014;20:408-414;

2. Platzbecker U, et. A. Lancet Oncol. 2017; 18:1338.

Modified extracellular domain ofActRIIB

HumanIgG1 Fcdomain

LuspaterceptActRIIB / IgG1 Fc recombinant

fusion protein

Cytoplasm

Nucleus

Erythroid maturation

Smad2/3

Complex

P

TGF-βsuperfamily

ligandActRIIB

MEDALIST TrialStudy Design – A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study

Data cutoff: May 8, 2018 Includes last subject randomized + 48 weeks.EPO, erythropoietin; HMA, hypomethylating agent; iMID, immunomodulatory drug; IWG, International Working Group; s.c., subcutaneously; SF3B1, splicing factor 3b subunit 1; WHO, World Health Organization.

Patient Population

• MDS-RS (WHO): ≥ 15% RS or ≥ 5% with SF3B1mutation

• < 5% blasts in bone marrow

• No del(5q) MDS

• IPSS-R Very Low-, Low-, or Intermediate-risk

• Prior ESA response

– Refractory, intolerant

– ESA naive: EPO > 200 U/L

• Average RBC transfusion burden ≥ 2 units/8 weeks

• No prior treatment with disease-modifying agents (e.g. iMIDs, HMAs)

Randomize 2:1

Luspatercept 1.0 mg/kg (s.c.) every 21 daysn = 153

Placebo (s.c.) every 21 daysn = 76

Dose titrated up to a maximum of 1.75 mg/kg

Disease & Response Assessment week 24 & every 6 months Treatment discontinued for lack of clinical benefit or disease

progression per IWG criteria; no crossover allowed

Subjects followed ≥ 3 years post final dose for AML progression, subsequent MDS treatment and overall survival

MEDALIST TrialPrimary Endpoint: Red Blood Cell Transfusion Independence ≥ 8 Weeks

RBC-TI ≥ 8 weeks Luspatercept

(n = 153)Placebo(n = 76)

Weeks 1–24, n (%) 58 (37.9) 10 (13.2)

95% CI 30.2–46.1 6.5–22.9

P valuea < 0.0001a Cochran–Mantel–Haenszel test stratified for average baseline RBC transfusion requirement (≥ 6 units vs < 6 units of RBCs/8 weeks) and baseline IPSS-R score (Very Low or Low vs Intermediate).CI, confidence interval.

MEDALIST TrialDuration of RBC-TI Response in Primary Endpoint Responders

a During indicated treatment period. Patients who maintained RBC-TI at the time of analysis are censored.

Duration of RBC-TIa (week)

Pro

ba

bilit

y o

f M

ain

tain

ing

RB

C-T

I

Number of patients

Luspatercept 58 49 37 29 22 18 10 6 3 2 1 1 0

Placebo 10 9 3 2 2 2 0

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 10 20 30 40 50 60 70 80 90 100 110 120

Luspatercept

Placebo

Censored

Median duration (weeks) (95% CI): 30.6 (20.6–40.6) vs 13.6 (9.1–54.9)

MEDALIST TrialSecondary Endpoint: Erythroid Response (HI-E)

Luspatercept(n = 153)

Placebo(n = 76)

Achieved HI-Ea (weeks 1–24), n (%) 81 (52.9) 9 (11.8)

Reduction of ≥ 4 RBC units/8 weeks(baseline transfusion burden ≥ 4 units/8 weeks) 52/107 (48.6) 8/56 (14.3)

Hb increase of ≥ 1.5 g/dL(baseline transfusion burden < 4 units/8 weeks) 29/46 (63.0) 1/20 (5.0)

95% CI 44.72–61.05 5.56–21.29

P valueb < 0.0001

Achieved HI-Ea (weeks 1–48), n (%) 90 (58.8) 13 (17.1)

Reduction of ≥ 4 RBC units/8 weeks(baseline RBC transfusion burden ≥ 4 units/8 weeks) 58/107 (54.2) 12/56 (21.4)

Hb increase of ≥ 1.5 g/dL(baseline RBC transfusion burden < 4 units/8 weeks) 32/46 (69.6) 1/20 (5.0)

95% CI 50.59–66.71 9.43–27.47

P valueb < 0.0001a Defined as the proportion of patients meeting the HI-E criteria per IWG 2006 criteria (Cheson et al. 2006) sustained over a consecutive 56-day period during the indicated treatment period. b Luspatercept compared with placebo, Cochran–Mantel–Haenszel test.

Imetelstat Treatment Leads to Durable Transfusion Independence in RBC Transfusion-Dependent,

Non-Del(5q) Lower Risk MDS Relapsed/Refractory to Erythropoiesis-Stimulating Agent Who Are

Lenalidomide and HMA Naive

David P. Steensma, MD1, Uwe Platzbecker, MD2, Koen Van Eygen, MD3, Azra Raza, MD4, Valeria Santini, MD5, Ulrich Germing, MD, PhD6, Patricia Font, MD7, Irina Samarina, MD8, Maria Díez-Campelo, MD, PhD9, Sylvain Thepot, MD10, Edo Vellenga, MD11, Mrinal M. Patnaik, MD, MBBS12, Jun Ho Jang, MD, PhD13,

Jacqueline Bussolari, PhD14, Laurie Sherman, BSN14, Libo Sun, PhD14, Helen Varsos, MS, RPh14, Esther Rose, MD14 and Pierre Fenaux, MD, PhD15

1Dana-Farber Cancer Institute (US), 2University Hospital Carl Gustav Carus, Dresden (DE), 3Algemeen Ziekenhuis Groeninge, Kortrijk (BE),

4Columbia University Medical Center (US), 5MDS Unit, AOU Careggi-University of Florence (IT), 6Heinrich-Heine-Universität, Düsseldorf (DE),

7Hospital General Universitario Gregorio Marañon, Madrid (ES), 8Emergency Hospital of Dzerzhinsk, Nizhny Novgorod (RU),

9The University Hospital of Salamanca (ES), 10CHU Angers (FR), 11University Medical Center Groningen (NE), 12Mayo Clinic, Rochester (US),

13Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (KO), 14Janssen Research & Development, LLC (US),

15Hôpital Saint-Louis, Université Paris (FR)

ASH 2018 Abstract #463

single arm

open label

Background: IMerge/NCT02598661 (Part 1) Study Design1

1o Endpoint: 8-Week RBC TI2o Endpoints: 24-Week RBC TI / Time to TI / TI duration / TR (HI-E: Transfusion Reduction by ≥ 4 RBC units over 8 weeks) / MDS response per IWG / Overall survival / Incidence of AML / SafetyExploratory: telomerase activity / hTERT / telomere length / genetic mutations

Pre-medication:diphenhydramine, hydrocortisone 100-200 mg (or equivalent)

Supportive care: RBC transfusions, myeloid growth factors per local guidelines

1. Fenaux P, et al. HemaSphere 2018;2(S1):S1557 [oral presentation]

Patients with MDS

• IPSS Low or Int-1• Relapsed / refractory to ESA or

ineligible for ESA• Transfusion dependent (≥4u RBC/8

weeks)• ANC ≥ 1.5 x 109/L • Platelets ≥ 75 x 109/L

ImetelstatTreatment

7.5 mg/kg IV q4w (2-hr infusion)

AML, acute myeloid leukemia; ANC, absolute neutrophil count; HI-E, hematologic improvement-erythroid; IWG, International Working Group; TI, transfusion independence; TR, transfusion reduction.

IMerge: Longest Transfusion-Free Interval

Parameters N=38

Rate of 8-week TI, n (%) 14 (37)

Rate of 24-week TI, n (%) 10 (26)

Median time to onset of TI (range), weeks 8.1 (0.1-33.1)

Median duration of TI (range), weeks NE (17.0-NE)

Among the patients achieving durable TI, all showed a Hbrise of ≥ 3.0 g/dL compared to baseline during the transfusion-free interval

Hb, hemoglobin; HI-E, hematologic improvement-erythroid; TI, transfusion independence; TR, transfusion reduction.

150

125

75

50

25

0Patients

24-week TI 8-week TI HI-E (TR) No response

24

8

Treatment Group: Imetelstat (N=38)

100

Lo

ng

es

t T

ran

sfu

sio

n F

ree

In

terv

al (W

ee

ks

)

AHSCT candidate

? AHSCT at time of HMA failure

HMA

Clinical trial

NO

Proposal for HR-MDS Treatment Algorithm

TET-2 MT VAF > 10%/ASXL-1 WT

P53 VAF > 40% P53 VAF < 20%

YES

YES NO

HMACytopenia/ Myeloblasts > 10%

HMA prior to AHSCT

YESNO

Observe prior to AHSCT

Decitabine

AHSCT

P53 clearance

Phase 1b/2 Combination Study of APR-246 and Azacitidine(AZA) in Patients with TP53 Mutant Myelodysplastic

Syndromes (MDS) and Acute Myeloid Leukemia (AML)

David A Sallman1, Amy DeZern2, David P Steensma3, Kendra Sweet1, Thomas Cluzeau4, Mikkael Sekkeres5, Guillermo

Garcia-Manero6, Gail Roboz7, Amy McLemore1, Kathy McGraw1, John Puskas1, Ling Zhang1, Chirag Bhagat8, Jiqiang

Yao9, Najla H Al Ali1, Eric Padron1, Roger Tell10, Jeffrey E. Lancet1, Pierre Fenaux11, Alan F List1 and Rami S Komrokji1

1Malignant Hematology Department, H. Lee Moffitt Cancer Center and Research

Institute, Tampa, FL, USA.; 2Sidney Kimmel Comprehensive Cancer Center, Johns

Hopkins University, Baltimore, MD, USA; 3Department of Medical Oncology, Dana

Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; 4Cote D’azur

University, Nice Sophia Antipolis University, Hematology Department, CHU Nice, Nice,

France; 5Department of Hematology and Medical Oncology, Cleveland Clinic,

Cleveland, OH, USA; 6Department of Leukemia, MD Anderson Cancer Center,

Houston, TX, USA; 7Weill Cornell Medical College, New York, NY, USA; 9Cancer

Informatics Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA; 10Aprea Therapeutics, Stockholm, Sweden; 11Hospital St Louis, Paris 7 University,

Paris, France.

2018 ASH Abstract # 3091

APR-246 (PRIMAMET) Restores Wild-type p53 Function

• Most TP53 gene mutations are single AA missense mutations in the DNA-binding domain

• APR-246 covalently binds to cysteines in mutant p53 or p63

• Reconstitutes WT conformation & function in mutant proteins by stabilizing protein folding

• Intrinsic & additive in vitro schedule-dependent cytotoxicity with azacitidine

Khoo et al., Nature Reviews Drug Discovery; 2014, 13, 217-36 .

Study Design

• TP53 mutant (mTP53) HMA naïve MDS and AML (≤ 30% blasts)

Treatment Duration and Response

The First-in-Class Anti-CD47 Antibody Hu5F9-G4 is Well Tolerated and Active Alone or with

Azacitidine in AML and MDS Patients: Initial Phase 1b Results

David A Sallman1, William Donnellan2, Adam Asch3, Daniel Lee4, Monzr Al Malki5, Guido Marcucci5, Daniel Pollyea6, Suman Kambhampati7, Rami Komrokji1, Joanna Van Elk8, Ming Lin8, James Y Chen8, Jens-Peter Volkmer8, Chris Takimoto8, Mark

Chao8, Paresh Vyas9

1Moffitt Cancer Center, Tampa, FL; 2Sarah Cannon Research Institute, Nashville, TN; 3University of Oklahoma, Oklahoma City, OK, City of Hope, Duarte, CA;

4Columbia University, New York, NY; 5City of Hope, Duarte, CA; 6University of Colorado, Denver, CO; 7Healthcare Midwest, Kansas City, MO;

8Forty Seven, Inc., Menlo Park, CA; 9University of Oxford, Oxford, UK

CONFIDENTIAL

Targeting Macrophages Leverages the Innate Immune System in the Fight Against Cancer

o CD47 is a “do not eat me” signal on cancers that enables macrophage immune evasion

o CD47 is the dominant macrophage checkpoint overexpressed on most cancers

o Increased CD47 expression predicts worse prognosis in AML patients

o 5F9 is a First-in-class Macrophage Immune Checkpoint Inhibitor Targeting CD47

o 5F9 Synergizes with Azacitidine to Induce Remissions in AML Xenograft Models

Majeti, Chao et al., Cell 2009

AML Patients

Macrophages are a key part of the innate immune

system serving as first responder cells:

o Phagocytose cells displaying abnormal “eat me” signals,

including cancer cells

o Recruit, activate, and present cancer cell antigens to T cells

CONFIDENTIAL

5F9005 Study Design: 5F9 Alone or in Combination with Azacitidine in AML

and MDS

o A 5F9 priming dose (1 mg/kg) and dose ramp up was utilized to mitigate on target

anemia

o 5F9 monotherapy safety was confirmed in r/r AML/MDS patients prior to

5F9+AZA combination

Relapsed/

refractory (r/r)

AML or MDS

5F9: 1, 30

mg/kg* twice

weekly

5F9: 1, 30

mg/kg* weekly

AZA: 75 mg/m2

D1-7

5F9 Monotherapy

Safety Run-in Cohort (N=10) 1) Safety of 5F9 alone or with AZA

2) Efficacy of 5F9 in r/r AML/MDS

and 5F9+AZA in untreated

AML/MDS

1) PK, PD and immunogenicity of 5F9

2) Additional measures of efficacy

(DOR, PFS, OS)

Primary objectives

Secondary objectives

1) To assess CD47 receptor

occupancy, markers of immune

cell activity, and molecular

profiling in AML/MDS

Exploratory objectives

Untreated AML

ineligible for

induction

chemotherapy

or untreated

MDS

intermediate to

very high risk

by IPSS-R

5F9 + AZA Combo

Safety Evaluation (N=6) Expansion (N=30)

5F9: 1, 30

mg/kg* weekly

AZA: 75 mg/m2

D1-7

*Dose ramp up from 1 to 30 mg/kg by week 2,then 30 mg/kg maintenance dosing

CONFIDENTIAL 26

Anti-Leukemic Activity is Observed with 5F9 Monotherapy and in Combination with AZA in AML and MDS

Response assessments per 2017 AML ELN criteria and 2006 IWG MDS criteria; Patients with at least one

post-treatment response assessment are shown

“-” not applicable

2 patients not shown due to missing

values

<5% blasts imputed as 2.5%

Best Overall

Response

R/R

AML/MD

5F9

mono

N=10

1L

AML

5F9+AZA

N=14

1L

MDS

5F9+AZA

N=11

ORR 1 (10%) 9 (64%) 11 (100%)

CR 0 5 (36%) 6 (55%)

CRi 0 2 (14%) -

PR 0 0 0

MLFS/

marrow CR1 (10%) 2 (14%)

4 (36%)

2 with

marrow

CR+HI

Hematologic

improvement

(HI)

- - 1 (9%)

SD 7 (70%) 5 (36%) 0

PD 2 (20%) 0 0

o 5F9 monotherapy has an ORR of 10% in r/r AML/MDS

o 5F9+AZA has an ORR of 100% in MDS, 64% in AML which compares favorably to AZA monotherapy

o ORR Median time to response is more rapid (1.9 months) than AZA alone

Patient

Be

st R

ela

tive

Ch

ange

fro

m B

ase

line

in

Bo

ne

Mar

row

Bla

st (

%)

5F9+AZA

+ AML patient

CONFIDENTIAL 27CONFIDENTIAL

Parameter 1L AML

N=14

1L MDS

N=11

RBC transfusion

independence9/14 (64%) -

Complete

cytogenetic

response in

responders*

2/7 (29%) 3/7 (43%)

MRD negativity in

responders3/9 (33%) 2/10 (20%)

Median duration of

response (months)

NR

(0.03+ –

8.3+)

NR

(0.5+ –

4.3+)

Median follow-up

[range] (months)

3.8 (1.9 –

10.3)

3.7 (2.5 –

6.8)

Minimal residual disease (MRD) was evaluated by multiparameter flow cytometry

Hematologic improvement (HI-E, HI-P, HI-N) defined per 2006 IWG MDS criteria

Cytogenetic response defined per 2003 and 2006 IWG criteria; NE: not reached

*Cytogenetic responses shown for all responding patients with abnormal

cytogenetics at baseline

“-” not applicable

Deep and Potential Durable Responses Seen in 5F9 + AZA Treated Patients

Time on therapy (months)

Pat

ien

t

5F9+AZA treated patients

*underwent transplant

**

**

*HI

HI

Hematologic

improvement HI

o No responding patient has relapsed or progressed on 5F9 + AZA

o Multiple patients have improved responses over time

o MRD negativity has been observed (time to MRD negativity ranged from 1.7 to 6.1 months)

o 5/20 (25%) of responding patients have successfully received an allogeneic stem cell transplant

o The longest patient in response is in CR 9+ months on therapy and ongoing

HI

CONFIDENTIAL 28

On Target Anemia is a Pharmacodynamic Effect and is Mitigated with a 5F9

Priming and Maintenance Dosing Regimen

Hemoglobin changes on 5F9+AZA therapy in AML/MDS

Ch

ange

in H

em

ogl

ob

in (

g/d

L) f

rom

Bas

elin

e-1

01

23

Baseline

o Aging RBCs can be cleared by CD47

blockade leading to an on target anemia

o A priming dose mitigates on target anemia

through a temporary/mild decline in

hemoglobin by clearing aged RBCs with

reticulocytosis

o Anemia returns to baseline with treatment

with 5F9 even at higher maintenance

doses (30mg/kg)

o A mild hemoglobin drop (mean of 0.5 g/dL)

with the priming dose was observed with

5F9+AZA

o Many patients have had hemoglobin

improvement and decrease in

transfusion frequency while on

5F9+AZA therapy

Primary failure (lack of primary response) 25%

• Clear evidence of disease progression on therapy or death on

treatment

• Median OS 4.7 mo (Rigosertib study), 5.5 mo (MCC database)

Secondary failure ≈ 75%

• Loss of initial response or probably only stable disease after 9 cycles.

• Median OS 6.9 mo (MCC database)

• 25% AML progression at time of failure

Defining HMA failure

Prognostic models after HMA failure

Nazha et al , Hematologica 2016

New HMAAgent mechanism Preliminary resultsCC-486 Oral azacitidine • In phase I study, 41 patients received SC and oral azacitidine. Dose-

limiting toxicity (grade 3/4 diarrhea) occurred at the 600-mg dose and

MTD was 480 mg. Overall response rate was 35% in previously treated

patients and 73% in previously untreated patients.

• In Phase 2, Patients with LR-MDS received 300 mg CC-486 once daily

for 14 days (n=28) or 21 days (n=27) of repeated 28-day cycles. Overall

response was attained by 36% of patients receiving 14-day dosing and

41% receiving 21-day dosing. RBC TI rates were similar with both dosing

schedules (31% and 38%, respectively).

SGI-110 dinucleotide of

decitabine and

deoxyguanosine that

protects it from

deamination

• In a phase I study that included 14 patients with MDSs after HMA failure,

SGI-110 had a 4.5-fold longer half-life than decitabine. An equivalent or

higher area under the curve was reached with lower Cmax compared

with reference levels from intravenous decitabine.

• A dose-dependent increase in demethylation was observed up to 60

mg/m2 daily for 5 days.

• In the phase II part of the study for treatment-naive elderly patients with

AML or refractory/relapsed AML, 43% and 16% remission rates were

reported.

ASTX727 Fixed dose oral cytidine

deaminase inhibitor

E7727 with oral

decitabine

• AEs are consistent with IV decitabine with no GI toxicity.

• ASTX727 is clinically active 33% response rate in phase I, 50% had prior

HMA.

• The fixed oral dose of 30 mg decitabine and 100 mg E7727 results in

decitabine AUC equivalent to 20 mg/m2 IV and will be further studied in a

Phase 2 trial in HMA naïve MDS

Savona et al, ASH 2015, abstract # 1683

Kantarjian HM, et al. ASH 2013. Abstract 497.Garcia Manero et al, J Clin Oncol. 2011 Jun 20; 29(18): 2521–2527

Garcia Manero et al , Leukemia 2016 Apr;30(4):889-96

Response, n/N (%) MDS Pts

(N = 17)

ORR* 10/17 (59)

CR† 1/11 (9)

PR† 1/11 (9)

mCR† 3/11 (27)

Any HI

Erythrocytes

Platelets

Neutrophils

Trilineage

improvement

Bilineage

improvement

5/17 (29)

3/15 (20)

4/12 (33)

4/10 (40)

2/5 (40)

2/5 (40)

Enasidenib in mIDH2 MDS: Response

• 7 of 13 pts (54%)

with prior HMA

responded to

enasidenib

• Median time to

response: 21 days

(range: 10-87)

Stein EM, et al. ASH 2016. Abstract 343.

*CR + PR + mCR + HI.†Investigator-assessed; pts had ≥ 5% BM blasts at BL.

Ivosidenib for mIDH-MDS

• 12 MDS patients demonstrated a 91.7% ORR and a CR rate of 41.7%.

• Among 13 patients progressed to AML after HMA failure CR/CRh (4/13) 33%

Out of the box

• Shifting HMA+Venetoclax or add on Venetoclax (n=19, ORR 47%, 56% proceeded to Allo-SCT) (unpublished data)

• RAS mutations- Trametinib?

• CBL mutations- Dasatinib?

Induction after HMA failure

Talati, et al. ASH 2018.

MDS: Lower risk

Upfront: first line

MCC 19872

“Commands Study”

Luspatercept (ACE-536) vs. ESA for

low risk MDS.

CRC: William Prada

PI: Komrokji

Light Blue: Actively Accruing

Gray: Closed to Accrual

Yellow: Long-Term Follow-Up

Purple: Pending

Green: Final Closed

Future considered

2nd line after ESA failure

MCC 18634

IIT: Ph. Ib/II LB-100 for

Low to Int.-1 MDS

Preferred for del 5 q len

failure

CRC: Lisa Nardelli

PI: Komrokji

ESA NaiveMCC 19939

Oral Decitabine

CRC: Willliam Prada

PI: Sallman

MCC 19430

Sponsor: TEW

Phase I/II TEW TGFB inhibitor

for lower risk MDS

CRC: Lisa Nardelli

PI: Dr. Komrokji

HMA candidate

MCC XXXX

Canakinumab/darbepoetin

CRC: TBD

PI: Sallman

MCC XXXX

Luspatercept

CRC: TBD

PI: komrokji

ESA failure

HMA failure

MCC 19658

SX682 for HMA failure

MDS

CRC: William Prada

PI: Sallman

A Phase 1b/2 Study Evaluating the Safety and Efficacy of Canakinumab with Darbepoetin alfa in Patients with Lower-Risk MDS who have Failed ESA

Dose Level Canakinumab (mg) Darbepoetin alpha (µg)

S.C q 4 weeks S.C q 2weeks

-1 75 300

1 (Starting dose) 150 300

2 300 300

Study population• Very low/low/intermediate R-IPSS risk MDS. • Transfusion dependent anemia.• ESA failure or low chance of response in non-del5q.• ESA and lenalidomide failure in del5q.

RP2DStage 1: 10 patients & Stage2: 19 patients

Phase 1b

(n=9-18)

Phase II

(n=29)

Primary end point • MTD & RP2D

Primary end point • HI-IWG 2016 criteria• safety

Correlative studies:• Determine recurrent gene mutations utilizing a targeted next generation sequencing (NGS) myeloid panel at study entry and serially throughout treatment to assess

changes in somatic mutation landscape. Comparison between responding and non-responding patients will be performed using qualitative analyses.

• To characterize in vivo IL-1 inhibition, as determined by inflammatory pathway analysis via serial high sensitivity CRP, un-neutralized IL-1, peripheral blood ASC specks, circulating oxidized mitochondrial DNA, S100A9 and comprehensive cytokine profiling.

• Evaluation of innate immune and pyroptosis biomarker indices including ASC specks by flow cytometry and Il-1, S100A9 and oxidized mitochondrial DNA by ELISA in PB plasma; ASC speck immunofluorescence on mononuclear cells by flow cytometry. In BM will evaluate changes in MDSC number by flow cytometry, colony forming capacity (CFC) and pyroptosis biomarkers.

PI: David Sallman

LB100: PP2A inhibitor

MDS: Higher risk

Upfront: first line

Light Blue: Actively Accruing

Gray: Closed to Accrual

Yellow: Long-Term Follow-Up

Purple: Pending

Green: Final Closed

Future considered

2nd line after standard therapy

MCC 19322

Ph. II Azacitidine and anti-CD47

monoclonal antibody

CRC: Yainet Sanchez

PI: Sallman

MCC xxxx

Phase III Azacitidine/Tim- MCC 19862

PRGN-3006 CD33 CART

CRC: ICEPI: Sallman

MCC 20039

NKG2D CAR-T

CRC: ICE

PI: Sallman

Immune Therapy

MCC 19825

IIT: MDS consortium

Phase III: Azactidine +/- APR

246 for p53 mutated MDS/AML

CRC: lisa Nardelli

PI Sallman

MCC 20061

Phase II: CPX-351 for HR-MDS

CRC: William Prada

PI Sallman

MCC 19658

SX682 for HMA failure MDS

CRC: William Prada

PI: Sallman

Questions?Rami.komrokji@moffitt.org